(1) Field of the Invention
The present application generally relates to the identification and use of gene expression profiles with clinical relevance to breast cancer. In particular, the application relates to ER+ breast cancer and the use of HoxB13 gene expression to evaluate the likely responsiveness of the cancer to treatment options.
(2) Description of the Related Art
Elevated expression of HoxB13 is a predictor for patient benefit of extended adjuvant endocrine therapy in estrogen receptor-positive (ER+) breast cancer (U.S. Patent Application Publication 2013/0281502). As such, ER+ breast tumors that have elevated HoxB13 are associated with permissiveness to responsiveness to extended endocrine therapy such as with a selective estrogen receptor modulator (SERM) (e.g., tamoxifen), a selective estrogen receptor down-regulator (SERD) (e.g., fulvestrant), or an aromatase inhibitor (AI) (e.g., letrozole). However, the signaling pathways yielding this permissiveness to endocrine therapy responsiveness within ER+ breast cancer tumors containing elevated HoxB13 expression are not known.
The most frequently altered intracellular growth signaling pathway in breast cancer is PI3K/Akt/mTOR (“mTOR”), which is implicated as a key driver of proliferation and survival, particularly in ER+ tumors.
The mTOR signaling pathway (FIG. 1) and the ER pathway are implicated in bidirectional crosstalk, in which intracellular signaling pathways stimulate ER signaling through phosphorylation and activation of the receptor and its cofactors. In addition, estrogen stimulation of breast cancer cells immediately up-regulates intracellular kinase signaling, indicating that signaling through cytoplasmic or membrane bound estrogen receptors is involved in activation of mTOR signaling.
Central to the mTOR pathway is mTOR Complex 1 (mTORC1), a protein complex that acts as a nutrient/energy/redox sensor and regulates cell growth, proliferation and metabolism through translational control of essential proteins. Important substrates of mTORC1 are the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases 1 and 2 (S6K1 and S6K2), which are involved in regulation of the translational machinery. S6K1 amplification and S6K1 protein overexpression are associated with a poor outcome in breast cancer.
Phosphorylation of 4EBP1 by mTORC1 dissociates 4EBP1 from EIF4E, enabling EIF4E to induce protein translation. Phosphorylated 4EBP1 (p4EBP1) is thus a marker of activated mTOR signaling, and high levels of p4EBP1 in tumors have been associated with a worse outcome in several malignancies, whereas non-phosphorylated 4EBP1 has been considered a tumor suppressor. High levels of S6K2 and/or 4EBP1 have also been associated with a poor breast cancer prognosis. Furthermore, high cytoplasmic levels of 4EBP1 protein appears to predict a poor prognosis, and has been associated with a decreased benefit from endocrine treatment.
The mTOR pathway can be activated by the protein Akt when Akt is phosphorylated by a phosphoinositide 3-kinase (PI3 kinase). A mutation of Akt or PI3 kinase can activate those proteins, which can activate the mTOR pathway. Inhibitors of mTOR, Akt or PI3-kinase are available or are in clinical development to treat cancers caused by those mutations.
There is a need to understand the pathways involved in establishing and maintaining the permissive state in ER+ breast cancer. The present invention addresses that need.